Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer.

Resistance to chemotherapeutic agents is a significant issue in the management of patients with breast cancer. Anthracyclines, although first used over 30 years ago, are still part of the standard chemotherapy for this disease. Subsequently, the taxanes heralded a new era in chemotherapy and have been used extensively in the treatment of metastatic breast cancer. Unfortunately, along with other constituents of combination chemotherapy for metastatic breast cancer such as cyclophosphamide, these agents become increasingly ineffective in progressive disease and tumours are then deemed to be drug resistant - frequently multidrug resistant. A number of processes have been identified that can underlie clinical drug resistance, and these largely stem from in vitro laboratory-based studies in human cancer cell lines. A large proportion of these studies have focused on multidrug resistance associated with resistance to natural product anticancer agents due to the presence of putative drug transporter proteins such as P-glycoprotein, MRP1, and BCRP. Other studies have highlighted mechanisms whereby breast cancer cells show resistance to chemotherapeutic agents by altered regulation of DNA repair processes, with many other factors influencing drug detoxification processes and altering drug targets. New developmental agents with improved specificity for tumour cells, such as trastuzumab, and those with low susceptibility to common tumour-resistance mechanisms, such as ixabepilone, have provided new hope for effective treatment of breast cancer. Ixabepilone is the first in a new class of neoplastics, the epothilones. With these developments in therapy, and the technology of gene expression profiling, the future holds more promise for the development of more effective treatment for metastatic breast cancer.